2-Decarboxy-2-hydroxymethyl-19-hydroxy-6-oxo-PGF1 compounds

ABSTRACT

The present invention provides novel 2-decarboxy-2-hydroxymethyl-19-hydroxy-6-oxo-PGF 1  compounds which are useful for pharmacological purposes, e.g., anti-asthmatic indications.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATION

The present invention is a divisional application of U.S. Ser. No.054,811, filed July 5, 1979, now U.S. Pat. No. 4,225,508.

BACKGROUND OF THE INVENTION

The present invention provides novel prostacyclin analogs. Particularly,the present invention relates to prostacyclin analogs substituted at theC-19 position by hydroxy.

Particularly, the present invention relates to2-decarboxy-2-hydroxymethyl-19-hydroxy-6-oxo-PGF₁ compounds. The novelprostacyclin analogs are useful for pharmacological purposes, e.g., asanti-asthmatic agents. The preparation and use of these compounds isincorporated here by reference from U.S. Ser. No. 054,811, filed July 5,1979 now U.S. Pat. No. 4,225,508.

PRIOR ART

For background on prostacyclin, see for example R. A. Johnson, et al.,Prostaglandins 12, 915-928 (1976) and R. A. Johnson, et al., J. Am.Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity,the references cited therein. For analogs of prostacyclin, see, forexample, J. Fried, et al., Proc. Natl. Acad. Sci. U.S.A. 74, 2199-2203,K. C. Nicolaou, et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson,J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima, et al., Tetra.Letters, 1978, (1977), and K. Kojima, et al., Tetra. Letters, 1978,3743-3746. Regarding the nomenclature for analogs of PGI₂, see R. A.Johnson, et al., Prostaglandins 15, 737-740 (1978).

SUMMARY OF THE INVENTION

The present invention particularly provides

a prostacyclin-type compound of the formula ##STR1## wherein D is--(CH₂)₂ --CO--CH₂ --L₂ -- or --CH₂ --CO--CH₂ --L₃ --

wherein L₂ is

(1) --(CH₂)_(j), wherein j is one to 4, inclusive,

(2) --(CH₂)_(q) --CF₂ --, wherein q is one, 2, or 3, or

(3) --CH═CH--,

wherein L₃ is

(1) --(CH₂)_(n) --, wherein n is one to 5, inclusive,

(2) --(CH₂)_(p) --CF₂ --, wherein p is 2, 3, or 4, or

(3) --CH₂ --CH═CH--;

wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH,

wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl;

wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro;

wherein X is

(1) trans-CH═CH--,

(2) cis-CHαCH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following compounds:

2-Decarboxy-2-hydroxymethyl-5-oxo-19-hydroxy-PGF₁,

2-Decarboxy-2-hydroxymethyl-5-oxo-16,16-difluoro-19-hydroxy-PGF₁,

2-Decarboxy-2-hydroxymethyl-6-oxo-19-hydroxy-PGF₁, and

2-Decarboxy-2-hydroxymethyl-6-oxo-16,16-difluoro-19-hydroxy-PGF₁.

I claim:
 1. A prostacyclin-type compound of the formula ##STR2## whereinD is --(CH₂)₂ --CO--CH₂ --L₂ -- or --CH₂ --CO--CH₂ --L₃ --wherein L₂is(1) --(CH₂)_(j), wherein j is one to 4, inclusive, (2) --(CH₂)_(q)--CF₂ --, wherein q is one, 2, or 3, or (3) --CH═CH--, wherein L₃ is(1)--(CH₂)_(n) --, wherein n is one to 5, inclusive, (2) --(CH₂)_(p) --CF₂--, wherein p is 2, 3, or 4, or (3) --CH₂ --CH═CH--;wherein Q is oxo,α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH, wherein R₄ is hydrogen or alkyl ofone to 4 carbon atoms, inclusive,wherein R₂ is hydrogen, hydroxyl, orhydroxymethyl; wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbonatoms, inclusive, or fluoro, being the same or different, with theproviso that one of R₅ and R₆ is fluoro only when the other is hydrogenor fluoro; wherein X is (1) trans-CH═CH--, (2) cis-CH═CH--, (3)--C.tbd.C--, or (4) --CH₂ CH₂ --.
 2. A compound according to claim 1,wherein D is--(CH₂)₂ --CO--CH₂ --L₂ --, wherein L₂ is --(CH₂)_(j),wherein j is one to 4, inclusive.
 3. A compound according to claim 2,wherein D is--(CH₂)₂ --CO--CH₂ --(CH₂)₂ --, Q is α-OH:β-H, R₂ ishydroxyl, and X is trans-CHαCH--. 4.2-Decarboxy-2-hydroxymethyl-5-oxo-19-hydroxy-PGF₁, a compound accordingto claim
 3. 5.2-Decarboxy-2-hydroxymethyl-5-oxo-16,16-difluoro-19-hydroxy-PGF₁, acompound according to claim
 3. 6. A compound according to claim 1,wherein D is--CH₂ --CO--CH₂ --L₃, wherein L₃ is --(CH₂)_(n) --, whereinn is one to 5, inclusive.
 7. A compound according to claim 6, wherein Dis--CH₂ --CO--CH₂ --(CH₂)₃ --, Q is α-OH:β-H, R₂ is hydroxyl, and X istrans-CH═CH--.
 8. 2-Decarboxy-2-hydroxymethyl-6-oxo-19-hydroxy-PGF₁, acompound according to claim
 7. 9.2-Decarboxy-2-hydroxymethyl-6-oxo-16,16-difluoro-19-hydroxy-PGF₁, acompound according to claim 7.